The present invention relates to a novel process for practically and conveniently producing a diphosphine oxide or diphosphonate. More specifically, the invention pertains to a novel process for practically and conveniently producing a diphosphine oxide or diphosphonate which is an intermediate for the synthesis of an optically active phosphine compound serving as an important component of an excellent catalyst for asymmetric synthesis reaction.
A number of reports have hitherto been made on transition metal complexes usable for asymmetric synthesis such as asymmetric hydrogenation reaction, asymmetric isomerization reaction or asymmetric hydrosilylation reaction. Among them, complexes of a transition metal such as ruthenium, rhodium, iridium or palladium each having an optically active tertiary phosphine compound as a ligand are known to have an excellent performance as a catalyst for asymmetric synthesis reaction.
In order to heighten the performance of these complexes as a catalyst for asymmetric synthesis reaction, phosphine compounds of various structures have so far been developed and reported (for example, The Chemical Society of Japan, ed., xe2x80x9cKagakusousetsu 32: Yuukikinzokusakutai no Kagakuxe2x80x9d, 232-237 (1982); Ryoji Noyori, xe2x80x9cAsymmetric Catalysis In Organic Synthesisxe2x80x9d, A Wiley-Interscience Publications). Among these various optically active phosphine compounds so far reported, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (which will hereinafter be abbreviated to xe2x80x9cBINAPxe2x80x9d) is one of excellent ligands of metallic complexes. A rhodium complex (JP-B-55-61973) and a ruthenium complex (JP-B-61-6390) containing this BINAP as a ligand have already been reported.
A process for synthesizing the above-described BINAP by brominating a racemic binaphthol by using a triphenylphosphine-dibromide at a high temperature (240 to 320xc2x0 C.), introducing it to the corresponding digrignard reagent, condensing the reagent with a diarylphosphinyl chloride compound to form the corresponding diphosphine oxide compound and, after optical resolution, reducing it into the corresponding tertiary diphosphine compound (a BINAP) by using a trichlorosilane as a reducing agent is known as an industrial process (H. Takaya, K. Mashima, K. Koyano, M. Yagi, H. Kumobayashi, T. Taketomi, S. Akutagawa, R. Noyori, xe2x80x9cJ. Org. Chem., 51, 629 (1986)).
As another known process for synthesizing a diphosphine compound is a process of reducing a substituted (2-nitrophenyl)diphenylphosphine oxide compound into the corresponding (2-aminophenyl)diphenylphosphine oxide compound, diazotizing and iodinating the resulting compound into the corresponding substituted (2-iodophenyl)diphenylphosphine oxide compound, dimerizing the resulting compound in the presence of copper into the corresponding diphosphine oxide compound, and after optical resolution, reducing it into the corresponding tertiary diphosphine compound by using trichlorosilane as a reducing agent (Japanese Language Laid-Open Publication (PCT) No. Hei 5-507503).
A process for obtaining a diphosphine oxide compound by reacting a phosphine oxide compound with a lithium or magnesium amide compound, and adding an oxidative metal salt to the resulting suspension is also known as a process for synthesizing a diphosphine oxide compound (JP-B-11-246576).
The conventionally known processes for producing a diphosphine compound are however accompanied with the drawbacks that a long production step is sometimes required depending on an intermediate used for its synthesis; this process includes a severe exothermic reaction; a yield of a desired optically active diphosphine compound is low; or this process is not utterly safe upon industrialization.
Synthesis of a diphosphine oxide or diphosphonate which is an intermediate for the production of a diphosphine compound also involves various problems upon industrialization such as long production step, low yield, and inclusion of a dangerous step generating severe heat.
For example, a process described in the above-described JP-B-11-246576 is dangerous because marked heat generation is recognized when an oxidative metal compound is added to a base-treated phosphine oxide. Addition of an oxidative metal compound, particularly, anhydrous ferrous chloride which is presumed to be particularly important, in portions for suppressing this heat generation is disadvantageous as an industrial operation, because this metal compound itself has high hygroscopicity.
There is accordingly a demand for the development of a practical and industrially-suited process for conveniently producing a diphosphine oxide or diphosphonate in a high yield, which process does not need a long preparation step, and is free of severe heat generation.
An object of the present invention is to provide a novel, safe and practical process for producing, easily in a high yield without generating severe heat, a diphosphine oxide or diphosphonate compound which is useful as an intermediate for the synthesis of a diphosphine compound useful as a ligand constituting a metallic complex catalyst having excellent performances such as chemical selectivity, enantioselectivity and catalytic activity in asymmetric synthesis reaction, particularly asymmetric hydrogenation reaction.
In order to achieve the above objects, the present inventors made extensive studies. As a result, it has been found that a diphosphine oxide or diphosphonate such as ((5,6),(5xe2x80x2,6xe2x80x2)-bis(methylenedioxy)biphenyl-2,2xe2x80x2-diyl)bis(diphenylphosphine oxide) (which will hereinafter be abbreviated as xe2x80x9cSEGPHOSOxe2x80x9d) or ((5,6),(5xe2x80x2,6xe2x80x2)-bis(methylenedioxy)biphenyl-2,2xe2x80x2-diyl)bis(diphenylphosphonate) can be synthesized in a short step, safely and in a high yield while suppressing a marked heat generation reaction, for example, by suspending an oxidative metal compound such as ferric chloride in a nonpolar solvent such as toluene, adding thereto a reaction mixture obtained by treating a phosphine or phosphonate such as diphenyl(3,4-methylenedioxyphenyl)phosphine oxide or diphenyl(3,4-methylenedioxyphenyl)phosphonate with a base such as lithium diisopropylamide and reacting them, leading to the completion of the invention.
In a first aspect of the present invention, there is thus provided a process for producing a diphosphine oxide or diphosphonate represented by the following formula (1): 
wherein, R1 represents a C1-4 alkyl group, a C5-8 cycloalkyl group, a phenyl group, a substituted phenyl group substituted with 1 to 5 substituents which may be the same or different and each selected arbitrarily from the group consisting of C1-4 alkyl groups, C1-4 alkoxy groups and a phenyl group, a naphthyl group which may be substituted with a C1-4 alkyl group or a C1-4 alkoxy group, a C1-4 alkoxy group, a phenoxy group, or a substituted phenoxy group substituted with 1 to 5 substituents which may be the same or different and each selected arbitrarily from the group consisting of C1-4 alkyl groups, C1-4 alkoxy groups and a phenyl group, which comprises treating, with a base, a phosphine oxide or phosphonate compound represented by the following formula (2): 
wherein, R1 has the same meaning as described above, and adding the thus-treated compound to a nonpolar solvent having an oxidative metal compound suspended therein so as to effect dimerization.
In a second aspect of the invention, there is also provided a process for producing a diphosphine oxide or diphosphonate represented by the formula (1), wherein in the above-described first invention, the base is selected from the group consisting of organolithium reagents, organomagnesium reagents such as Grignard reagents and magnesiumamides.
In a third aspect of the invention, there is also provided a process for producing a diphosphine oxide or diphosphonate represented by the formula (1), wherein in the above-described first invention, the oxidative metal compound is at least one selected from the group consisting of metal salts and metallic complex compounds each made of iron, copper, ruthenium, cobalt, nickel, vanadium, molybdenum, manganese or titanium.
In a fourth aspect of the invention, there is also provided a process for producing a diphosphine oxide or diphosphonate represented by the formula (1), wherein in the above-described first invention, the nonpolar solvent to have an oxidative metal compound suspended therein is at least one selected from the group consisting of aliphatic hydrocarbons and aromatic hydrocarbons.
The production process of the above-described inventions can be indicated by the following reaction scheme: 
The diphosphine oxide or diphosphonate represented by the above-described formula (1) will next be described more specifically. With regards to R1 in the formula, examples of the C1-4 alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl; those of the C5-8 cycloalkyl group include cyclopenthyl, 2,5-dimethylcyclopenthyl, 3,4-dimethylcyclopenthyl, cyclohexyl, 4-methylcyclohexyl, 2,6-dimethylcyclohexyl, 3,5-dimethylcyclohexyl, 4,4-dimethylcyclohexyl and cycloheptyl; those of the phenyl or substituted phenyl include phenyl, p-tolyl, p-methoxyphenyl, p-trifluoromethylphenyl, p-fluorophenyl, p-dimethylaminophenyl, p-t-butylphenyl, 3,5-dimethylphenyl, 3,5-di-t-butylphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethyl-4-methoxyphenyl, 3,5-di-t-butyl-4-methoxyphenyl, 3,5-ditrifluoromethylphenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, pentafluorophenyl and biphenyl; those of the naphthyl or substituted naphthyl include xcex1-naphthyl, xcex2-naphthyl, 6-methoxy-xcex1-naphthyl and 6-methoxy-xcex2-naphthyl; those of the C1-4 alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and t-butoxy; and those of the phenyloxy or substituted phenyloxy group include phenyloxy, p-tolyloxy and p-methoxyphenyloxy.
The diphosphine oxide or diphosphonate represented by the formula (1) is preferred as an intermediate for producing a diphosphine compound useful as a catalyst for asymmetric synthesis reaction. Specific examples of such a compound include:
(a) (xc2x1)-((5,6),(5xe2x80x2,6xe2x80x2)-bis(methylenedioxy)biphenyl-2,2xe2x80x2-diyl)bis(diphenylphosphine oxide) (SEGPHOSO),
(b) (xc2x1)-((5,6),(5xe2x80x2,6xe2x80x2)-bis(methylenedioxy)biphenyl-2,2xe2x80x2-diyl)bis(bis(3,5-dimethylphenyl)phosphine oxide),
(c) (xc2x1)-((5,6),(5xe2x80x2,6xe2x80x2)-bis(methylenedioxy)biphenyl-2,2xe2x80x2-diyl)bis(bis(3,5-di-t-butyl-4-methoxyphenyl)phosphine oxide),
(d) (xc2x1)-((5,6),(5xe2x80x2,6xe2x80x2)-bis(methylenedioxy)biphenyl-2,2xe2x80x2-diyl)bis(bis(4-methoxyphenyl)phosphine oxide),
(e) (xc2x1)-((5,6),(5xe2x80x2,6xe2x80x2)-bis(methylenedioxy)biphenyl-2,2xe2x80x2-diyl)bis(dicyclohexylphopshine oxide),
(f) (xc2x1)-((5,6),(5xe2x80x2,6xe2x80x2)-bis(methylenedioxy)biphenyl-2,2xe2x80x2-diyl)bis(bis(3,5-di-t-butylphenyl)phosphine oxide), and
(g) (xc2x1)-((5,6),(5xe2x80x2,6xe2x80x2)-bis(methylenedioxy)biphenyl-2,2xe2x80x2-diyl)bis(diphenyl phosphonate).
Production processes of the invention including that of a phosphine oxide or phosphonate represented by the above-described formula (2) will next be described more specifically.
In the first place, a phosphine oxide represented by the formula (2) can be synthesized by a process analogous to a known process, for example, that described in J. J. Monagle, et al., xe2x80x9cJournal of Organic Chemistry, 32, 2477 (1967)xe2x80x9d.
A phosphonate compound represented by the formula (2) can be synthesized easily by a process known per se in the art or an analogous process thereto. One of the examples of the production process is to add dropwise a chlorophosphate compound represented by the formula (3): 
wherein, R2 represents a C1-4 alkyl group, a phenyl group or a substituted phenyl group substituted with 1 to 5 substituents which may be the same or different and are selected arbitrarily from the group consisting of C1-4 alkyl groups, C1-4 alkoxy groups and a phenyl group to a solution of a Grignard reagent or lithium reagent represented by the following formula (4): 
wherein, M represents magnesium or lithium, X represents a halogen atom and n stands for 0 or 1, in tetrahydrofuran, dioxane, ether, toluene or hexane at 30 to 40xc2x0 C. and reacting them at room temperature for 12 to 18 hours. Compounds employed for the above-described synthesis are easily available by the ordinary preparation process.
In the present invention, prior to dimerization of a phosphine oxide or phosphonate represented by the formula (2), it is anionized. This anion formation can be conducted in a manner known per se in the art. One of the examples is to react a phosphine oxide compound or phosphonate compound with at least 1 equivalent, preferably 1.2 to 2.0 equivalents of a base selected from organolithium reagents, organomagnesium reagents such as Grignard reagents and magnesiumamides in a solvent such as ether, aliphatic hydrocarbon or aromatic hydrocarbon, or mixture thereof at xe2x88x925xc2x0 C., preferably xe2x88x9278 to xe2x88x9215xc2x0 C.
Examples of the organolithium reagent include lithium alkyl amides, alkyl lithiums and allyl lithiums; those of the organomagnesium reagent include magnesium alkyl amides. Preferred examples of the base selected from these organolithium reagents, Grignard reagents and organomagnesium reagents include lithium diethyl amide, lithium diisopropyl amide (which will hereinafter be abbreviated as xe2x80x9cLDAxe2x80x9d), methyl lithium, butyl lithium, phenyl lithium, C1-5 alkyl magnesium halides, substituted or unsubstituted phenyl magnesium halides, magnesium diethyl amide and magnesium diisopropyl amide. Among them, LDA is more preferred.
Preferred examples of the ether, aliphatic hydrocarbon or aromatic hydrocarbon solvent include tetrahydrofuran (which will hereinafter be abbreviated as xe2x80x9cTHFxe2x80x9d), dioxane, diethyl ether, toluene, hexane and heptane, of which THF is more preferred.
The target product, that is, diphosphine oxide or diphosphonate represented by the formula (1) can be prepared in the following manner. Described specifically, the anion solution prepared in the above-described manner is reacted at 50xc2x0 C. or less, preferably xe2x88x925 to 15xc2x0 C. with a mixture obtained by suspending at least 1 equivalent, more preferably 1.2 to 2.0 equivalents (the number of the equivalent may be the same or different from the equivalent of the base) of an oxidative metal compound in an aliphatic or aromatic hydrocarbon.
The above-described oxidative metal compound is selected from oxidative salts or complex compounds of a metal selected from iron, copper, ruthenium, cobalt, nickel, vanadium, molybdenum, manganese or titanium, that is, oxidizing agents. Preferred examples of such an oxidative compound include salts and complex compounds of a metal selected from trivalent iron, divalent copper, trivalent ruthenium, trivalent cobalt, divalent nickel, trivalent, tetravalent, pentavalent vanadium, trivalent, tetravalent, pentavalent or hexavalent molybdenum, trivalent, tetravalent, pentavalent or hexavalent manganese and trivalent or tetravalent titanium. More preferred are chlorides, bromides, iodides, nitrates, sulfates, perchlorates, acetates, oxalates or acetylacetone complexes of such a metal, bipyridyl or phenanthrene complex of such a metal salt, with iron trichloride, iron tribromide, iron triiodide, copper dichloride, copper dibromide and copper diiodide being further more preferred.
Examples of the aliphatic or aromatic hydrocarbon which is a nonpolar solvent for suspending therein an oxidative metal compound include pentane, hexane, heptane, octane, cyclohexane, methylcyclohexane, benzene, toluene and xylene, of which toluene is particularly preferred.
A description will next be made of a novel production process of a diphosphine oxide compound according to the invention by using, as a typical example, the production process of, among the compounds embraced by the invention, SEGPHOSO represented by the below-described formula (5) (wherein, Ph represents a phenyl group) which is an intermediate useful for the preparation of (xe2x88x92) or (+)-((5,6),(5xe2x80x2,6xe2x80x2)-bis(methylenedioxy)biphenyl-2,2xe2x80x2-diyl)bis(diphenylphosphine) (which will hereinafter be abbreviated to xe2x80x9cSEGPHOSxe2x80x9d) in order to simplify this description. It should however be borne in mind that this example is merely a typical example of the invention and the invention is not limited to it. 
Diphenyl(3,4-methylenedioxyphenyl)phosphine oxide represented by the following formula (7) is prepared by adding dropwise a tetrahydrofuran solution of one equivalent of 3,4-methylenedioxybromobenzene represented by the following formula (6) to a magnesium piece at 40xc2x0 C. or less, reacting them at room temperature for at least 3 hours to form a Grignard reagent, adding one equivalent of diphenylphosphinyl chloride to the resulting Grignard reagent at 40xc2x0 C. or less, and reacting them at room temperature for 12 to 18 hours. 
Alternatively, the diphenyl(3,4-methylenedioxyphenyl)phosphine oxide represented by the formula (7) can be prepared by the following process.
That is, diphenyl(3,4-methylenedioxyphenyl)phosphonate represented by the following formula (8) is prepared by adding dropwise a tetrahydrofuran solution of one equivalent of 3,4-methylenedioxybromobenzene (6) to a magnesium piece at 40xc2x0 C. or less, reacting them at room temperature for at least 3 hours to form a Grignard reagent, adding the resulting reagent to a THF solution of one equivalent of diphenylphosphoryl chloride, and reacting them at room temperature for 12 to 18 hours. Then, to this compound, a THF solution of 2.5 equivalents of phenylmagnesium bromide is added dropwise at 5xc2x0 C. or less and they are reacted at room temperature for at least 12 to 18 hours, whereby the diphenyl(3,4-methylenedioxyphenyl)phosphine oxide (7) is prepared. 
The resulting phosphine oxide (7) is then dissolved in THF and a THF solution of 1.2 equivalents of lithium diisopropyl amide is allowed to act on the resulting solution at xe2x88x9215xc2x0 C. The reaction mixture is added dropwise to a toluene suspension of 1.2 equivalents of iron trichloride (anhydride) at a rate maintaining the temperature at 5xc2x0 C. of less and they are reacted, whereby the target SEGPHOSO can be produced in a high yield.
The production process of the invention makes it possible to conveniently prepare, in a high yield, a diphosphine oxide or diphosphonate represented by the formula (1) by a short step without generating severe heat. The process of the invention is therefore industrially useful for the production of an intermediate for the synthesis of an optically active phosphine compound, particularly SEGPHOS, which serves as an important component of a catalyst for asymmetric synthesis reaction.
The present invention will hereinafter be described in further detail by Examples. It should however be borne in mind that the invention is not limited by them.
Following are apparatuses used for the measurement of physical properties in the following Examples and Comparative Examples.
Nuclear magnetic resonance
1H NMR
Bruker AM400 (400 MHz)
31P NMR
Bruker AM400 (160 MHz)
Yanaco MP-500D
Melting point
High-performance liquid chromatography HPLC
Apparatus: LC10ATandSPD10A (Shimadzu Corporation)
Column: Inertsil 100-5 (4.6xc3x97230 mm) (GL Science)
Eluate: hexane:2-propanol=95:5
Flow rate: 0.5 ml/min
Detection wavelength: 254 nm